Pain - particularly chronic pain - is a major cause of morbidity, especially in patients with cancer or neuropathic pain. The goal of this research is to develop prolonged duration local anesthetics (PDLA) that would provide local anesthesia lasting days to weeks from a single injection, depending on the clinical context (perioperative vs. chronic pain). Our strategy has been to use a variety of sustained release vehicles to deliver site 1 sodium channel blockers (S1SCBs) such as saxitoxin (STX) and tetrodotoxin (TTX) in combination with compounds that are known to have synergistic or adjunctive effects on the duration of nerve blockade, such as conventional local anesthetics and steroids. To date, this line of inquiry has been very productive; since the current R01 began 3.5 years ago, we have produced 29 publications, and met or exceeded the goals of our Specific Aims. Our base formulation is a liposome containing S1SCBs and other drugs, where we have shown we can obtain sciatic nerve blocks in the rat lasting a week with minimal systemic and local toxicity. We propose a spectrum of potential modifications to produce yet longer blocks while maintaining safety. An equally important aim will be the in vivo assessment of the efficacy and systemic toxicity of these new formulations by neurobehavioral tests in rats and rabbits, by following serum drug levels. Another crucial aspect of the research, which has not received sufficient attention, will be to study the development of inflammation, myotoxicity, and neurotoxicity with these formulations, using histological and toxicogenomic approaches.